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ACIP: Use of BCG Vaccines in the Control of Tuberculosis: A Joint
Statement by the ACIP and the Advisory Committee for Elimination of
Tuberculosis

MMWR 37(43);663-664,669-675

Publication date: 11/04/1988

Table of Contents

Article

Since 1979, when the last Immunization Practices Advisory Committee
(ACIP) statement on vaccination with Bacillus of Calmette and
Guerin (BCG*) was published, additional data have been published
on the epidemiology of tuberculosis (TB) in the United States and on
the efficacy of childhood BCG vaccines. As a result, ACIP and the
Advisory Committee for Elimination of Tuberculosis have issued the
following educational update on BCG vaccines.**

Immunization with BCG vaccine lowers the risk of serious complications
of primary TB in children (1-4). However, BCG vaccination should be
considered only for children with negative tuberculin skin tests who
fall into the following categories: 1) those who cannot be placed on
isoniazid preventive therapy but who have continuous exposure to
persons with active disease; 2) those with continuous exposure to
patients with organisms resistant to isoniazid and rifampin; or 3)
those belonging to groups with exceptionally high annual rates of new
infection (i.e., greater than 1% per year).

BCG vaccination is no longer recommended for health-care workers or
other adults at high risk for acquiring TB infection. In addition, BCG
should not be given to persons who are immunocompromised, including
those with human immunodeficiency virus (HIV) infection.

INTRODUCTION

Transmission and Pathogenesis of TB

TB is a bacterial disease caused by organisms of the Mycobacterium
tuberculosis complex (i.e., M. tuberculosis, M. bovis, M. africanum).
It is transmitted primarily by airborne droplets; infection occurs when
susceptible persons inhale infectious droplets produced by the
exhalations of persons with respiratory tract TB. The risk for
infection is directly related to duration and intensity of exposure to
air contaminated with these droplets. TB infection usually begins in
the lungs and spreads to the hilar lymph nodes, then to the blood
stream. Thus, disease can occur in any organ of the body. Most infected
persons react to the purified protein derivative (PPD) tuberculin skin
test, and 5%-40% will develop clinically apparent TB. Infection is more
likely to progress to clinical disease in the presence of certain risk
factors, including younger and older ages, male sex, infection within
the past 2 years, leanness, and suppression of cell-mediated immunity.

TB can be presumptively diagnosed if acid-fast bacilli are found in
sputum, body fluids, or tissue or if at least two of three other
conditions are met: 1) symptoms are compatible with TB; 2) chest
radiograph is abnormal or abnormalities are found on physical
examination; or 3) reaction to the tuberculin skin test is positive.
Definitive diagnosis requires isolation and identification of organisms
of the M. tuberculosis complex from a clinical specimen. Diagnosis of
extrapulmonary TB is more difficult because it requires tissue biopsies
or body fluids (e.g., spinal fluid) that usually contain only a few
organisms.

Epidemiology of TB in the United States

TB in the United States has declined approximately 6% per year since
nationwide reporting began in 1953. However, in 1986, the morbidity
rate for TB increased slightly to 9.4/100,000, a rate 82% lower than
that for 1953 but 1.1% higher than the 1985 rate. A total of 22,768
cases were reported (5), and approximately 80% were pulmonary disease.

Untreated TB is fatal in up to 50% of cases. However, chemotherapy has
helped reduce the case-mortality rate 94% since 1953. In 1984, the most
recent year for which final mortality data are available, 1729 deaths
were attributed to TB, representing a mortality rate of 0.7/100,000
population.

Prevalence of TB infection and disease varies for different segments
of the population. Disease rates are twice as high in males as in
females and increase sharply with age in both sexes and all races.
Groups at high risk for TB include most racial/ethnic minorities,
immigrants from countries with a high prevalence of TB, the homeless
population, close contacts of persons with pulmonary TB, and persons
with HIV infection. In 1986, 62% of all TB cases occurred in
racial/ethnic minorities, and over 20% of all cases were in
foreign-born persons (5). Although the prevalence of active TB in the
homeless population is difficult to assess, surveillance of selected
clinics and shelters showed infection rates between 1.6% and 6.8% (6).
Based on 1985 data from U.S. health departments, 29% of close contacts
of TB patients were infected at the time the patients were diagnosed
(7). In addition, the estimated risk for active TB in persons with
symptomatic HIV infection is 100-200 times greater than that of persons
in the general population (8). Persons with asymptomatic HIV infection
and M. tuberculosis infection may have an equally high risk for
developing clinical disease.

In 1985, the 1261 cases of TB in children < 15 years of age accounted
for 5.7% of cases in all age groups. Eighty percent of these were among
racial/ethnic minorities (9). One fourth (315) of all childhood cases
were extrapulmonary; of these, 41 cases were meningeal, and 17 were
miliary. Childhood cases of TB meningitis and miliary TB remained
stable between 1981 and 1985, averaging 55 cases annually.

In the past, TB was regarded as an occupational hazard for health-care
workers, who had higher rates of infection and disease than persons of
the same age groups in the general population. Although these rates
have decreased over time, persons who work with high-risk patients or in
high-prevalence communities still may be at risk for new infection,
defined as conversion from a negative to a positive tuberculin skin test
(10-18). However, in recent studies, which found increased conversion
rates among health-care personnel, rates were highest in health-care
workers who did not have patient contact (10,11), suggesting that
conversion resulted from community-acquired infection with M.
tuberculosis or exposure to nontuberculous mycobacteria rather than from
occupational exposure.

Control of TB

There are four general strategies for controlling TB:

1. The most important and universally applied strategy is the early identification and treatment of persons with infectious TB. This strategy not only cures the affected person but also renders the patient noncontagious within a few weeks. Thus, case-finding and treatment programs have both clinical and public health benefits(19).

2. Identifying and treating persons with noncontagious TB (such as extrapulmonary disease, primary pulmonary disease in children,bacteriologically unconfirmed pulmonary disease, and tuberculous infection) can prevent infectious cases (20). Therapy to prevent progression of infection to clinical disease is particularly useful in countries, such as the United States, where the risk of new infection is low.

3. Use of ventilation and ultraviolet lights will decontaminate air containing infectious droplet nuclei. Because sites of potential transmission of tubercle bacilli are numerous and difficult to identify in advance, this strategy is used routinely only where the risk of transmission is known to be exceptionally high. Some of theses areas include mycobacteriology laboratories, sputum induction cubicles, chest clinic waiting areas, and selected shelters for the homeless. To be effective, ventilation systems
and ultraviolet lights must be properly maintained.

4. In the United States, BCG vaccination is recommended only for uninfected children who are at unavoidable risk of exposure to TB and for whom other methods of prevention and control have failed or are not feasible.

BCG VACCINES

BCG was derived from a strain of M. bovis attenuated through years of
serial passage in culture by Calmette and Guerin at the Pasteur
Institute in Lille, France. It was first administered to humans in
1921. Many BCG vaccines are available worldwide; all are derived from
the original strain but vary in cultural characteristics and in ability
to induce sensitization to tuberculin. BCG vaccines vary because of
genetic changes in the bacterial strains and because of differences in
techniques of production, in methods and routes of vaccine
administration, and in characteristics of the populations and
environments in which BCG vaccines have been studied.

Production standards for BCG vaccines, set by the Food and Drug
Administration, specify that they be freeze-dried products containing
live bacteria from a documented strain of BCG. The strain must
demonstrate various specified characteristics of safety and potency in
animals and induce tuberculin sensitivity in guinea pigs and humans.
The vaccines currently available in the United States have been
evaluated only for their ability to induce a delayed hypersensitivity
state.

Vaccine Efficacy Studies

BCG vaccines vary substantially in efficacy. Different preparations
of liquid BCG used in controlled community trials conducted before 1955
gave estimated efficacies ranging from -56% and 80% (21). In 1969, a
large controlled trail was begun in Madras (Chingleput) in south India
to estimate the efficacy of two strains of freeze-dried BCG vaccine and
two different doses. After 15 years of follow-up, the risk of sputum-
positive pulmonary TB in persons vaccinated with BCG was not lower than
that in persons given placebo (22).

Although randomized controlled trials are the most reliable method for
assessing vaccine efficacy, less precise estimates can be obtained more
quickly and less expensively by observational studies (case-control,
historical cohort, and cross-sectional studies) in areas where
vaccination is performed at birth. Data from such studies show that the
incidence of tuberculous meningitis and miliary TB is 52%-100% lower and
that the incidence of pulmonary TB is 2%-80% lower in vaccinated
children < 15 years of age than in unvaccinated controls (1-4,23,24).
However, because vaccination is not allocated randomly in observational
studies, disproportionate exposure to TB may distort the estimates of
vaccine efficacy.

Side Effects and Adverse Reactions

BCG rarely causes serious complications. Side effects vary by vaccine
strain; they also vary for the same strain over time. Side effects
occur in 1%-10% of vaccinated persons and usually include severe or
prolonged ulceration at the vaccination site, lymphadenitis, and lupus
vulgaris. The risk of side effects is greater with more potent
vaccines. Some vaccine strains have caused osteomyelitis in one case
per million doses administered. Disseminated BCG infection and death
have occurred in one to 10 cases per 10 million doses administered,
although this problem is restricted almost exclusively to persons with
impaired immunity.

Data on adverse reactions may pertain to the vaccines licensed in the
United States. The reported frequency of complications has varied,
depending in part on the intensity of the surveillance effort.

In persons with tuberculous infections, the response to BCG vaccine is
accelerated. This accelerated response is generally characterized by
the appearance of induration >5 mm in diameter within 24-48 hours after
vaccination, formation of a pustule within 5-7 days, and scab formation
and healing in 10-15 days (25). The normal response to BCG vaccine
begins 2-3 weeks after vaccination. Scar formation and healing occur
within 3 months.

Interpretation of Tuberculin Test Following BCG Vaccination

The size of tuberculin skin test reactions caused by BCG vaccination
(i.e., postvaccination sensitivity) varies by strain and dose of
vaccine, age and nutritional status at vaccination, number of years
since vaccination, and frequency of tuberculin testing. Mean size of
skin test reactions in BCG-vaccinated children range from 3 mm to 19 mm
(26-35). The presence or size of postvaccination tuberculin skin test
reactions does not reliably predict the degree of protection afforded by
BCG (36).

After BCG vaccination, it is usually not possible to distinguish
between a tuberculin skin test reaction caused by virulent mycobacterial
infection or by vaccination itself (37). Therefore, TB should be
included in the differential diagnosis of any TB-like illness,
especially if the person has been recently exposed to a person with
infectious TB or received BCG several years before being tuberculin
tested (38).

General guidelines exist for interpreting tuberculin skin test
reactions in BCG vaccine recipients. The probability that a skin test
reaction results from exposure to M. tuberculosis increases 1) as the
size of the reaction increases, 2) when the patient is a contact of a
person with TB, especially if that person has infected others, 3) when
there is a family history of TB or when the patient's country of origin
has a high TB prevalence, and 4) as the length of time between
vaccination and tuberculin testing increases (38). For example, a
positive skin test (>10 mm) usually can be attributed to M. tuberculosis
infection if the vaccinated person is in a group at high risk for TB or
has known exposure to a person with infectious TB. However, in
vaccinated persons who do not belong to groups at high risk for infection
and have no known exposure, a positive skin test reaction probably does
not indicate recent infection with M. tuberculosis.

GENERAL RECOMMENDATIONS

In the United States, the general population is at low risk for
acquiring tuberculous infection. Furthermore, TB can be controlled
successfully in most high-risk groups by modern methods of case
detection, chemotherapy, and preventive therapy. In most population
groups, prevention of TB is most reliably accomplished by periodic
Mantoux testing with PPD tuberculin for high-risk children and adults
and with administration of preventive therapy to those whose skin test
reactions convert from negative to positive. Preventive chemotherapy
should also be given to tuberculin-positive persons who are contacts of
persons with infectious TB and to other high-risk tuberculin-positive
persons (39). Therefore, a BCG vaccination policy for the entire
population is not indicated. However, BCG vaccination may contribute to
TB control in selected population groups. For example, it may benefit
uninfected children who are a high risk for continuous or repeated
exposure to infectious persons who remain undetected or untreated.

Recommended Vaccine Recipients

Exposed tuberculin skin-test-negative infants and children. BCG
vaccination is strongly recommended for infants and children with
negative tuberculin skin tests who 1) are at high risk of intimate and
prolonged exposure to persistently untreated or ineffectively treated
patients with infectious pulmonary TB, cannot be removed from the source
of exposure, and cannot be placed on long-term preventive therapy, or 2)
are continuously exposed to persons with TB who have bacilli resistant
to isoniazid and rifampin.

Groups with an excessive rate of new infections. BCG vaccination is
also recommended for tuberculin-negative infants and children in groups
in which the rate of new infections exceeds 1% per year (40) and for
whom the usual surveillance and treatment programs have been attempted
but are not operationally feasible. These groups include persons
without regular access to health care, those for whom usual health care
is culturally or socially unacceptable, or groups who have demonstrated
an inability to effectively use existing accessible care.

Discontinued Recommendation for Health-Care Workers

In the past, BCG vaccine was recommended for health-care workers, who
as a group experienced high rates of new infections. However, BCG is no
longer recommended for this group. Instead, health-care workers should
be protected by adequate surveillance by periodic tuberculin skin
testing (41) and isoniazid preventive therapy for all skin-test-positive
health-care workers who are a high risk for developing disease. These
persons include recent skin test converters and workers who are close
contacts of TB patients or those who have medical conditions such as
diabetes, renal failure, or immunosuppression associated with therapy
or disease (39). In addition, hospital infection control measures,
especially the prompt identification and implementation of precautions
for patients with suspected TB, will help reduce the risk of TB
transmission to health-care workers (42).

Vaccine Availability

Two BCG vaccine strains licensed in the United States are available.
The Glaxo strain is available from Quad Pharmaceuticals, Inc.,
Indianapolis. The Tice strain is available from Bionetics Research,
Inc., Chicago, or Antigen Supply House, Northridge, California.

Vaccine Dose and Administration

BCG should be reserved for persons whose skin test is negative to 5
tuberculin units of PPD tuberculin. The Glaxo strain is administered
intradermally and the Tice strain percutaneously. Vaccination should be
administered only by the route indicated in the package labeling and
only in the suggested dose.

Infants < 30 days old should receive one half the usual dose. If the
indications for vaccination persist, they should receive a full dose at
1 year of age.

Freeze-dried vaccine should be reconstituted, protected from exposure
to light, refrigerated when not in use, and used within 8 hours.

Contraindications to Use

BCG should not be given to persons 1) whose immunologic responses are
impaired because of congenital immunodeficiency, HIV infection,
leukemia, lymphoma, or generalized malignancy or 2) whose immunologic
responses have been suppressed by steroids, alkylating agents,
antimetabolites, or radiation.

BCG vaccine should be administered with caution to persons in groups
at high risk for HIV infection. An AIDS patient was reported to have
developed disseminated M. bovis disease after vaccination with BCG (43).
Three infants with symptomatic HIV infection were reported to have
developed BCG adenitis after vaccination (44); however, disseminated BCG
disease has not been reported in persons with asymptomatic HIV
infection.

Theoretically, persons with asymptomatic HIV infection may be at
greater risk for complications from BCG vaccine, but data are
inconclusive regarding this elevated risk. The World Health
Organization has recommended that in populations where the risk of
tuberculosis is high, HIV-infected children who are asymptomatic should
receive BCG vaccine at birth or as soon as possible thereafter. BCG
vaccine should not be given to children with symptomatic HIV infection
(45). In populations where the risk of TB is low, BCG vaccine should be
withheld from persons known or suspected to be infected with HIV (45).
The latter recommendation would apply to most populations in the United
States for whom BCG might be considered.

Use in Pregnancy

Although harmful effects of BCG on the fetus have not been observed,
women should avoid vaccination during pregnancy.

SURVEILLANCE

All suspected adverse reactions to BCG should be reported to the
manufacturer and to the Office of Biologics Research, Center for
Biologics Evaluation and Research, Food and Drug Administration,
Bethesda, Maryland. These reactions occasionally occur > 1 year after
vaccination.

References

Romanus V. Tuberculosis in Bacillus Calmette-Guerin-immunized
and unimmunized children in Sweden: a ten-year evaluation following
the cessation of general Bacillus Calmette-Guerin immunization of
the newborn in 1975. Pediatr Infect Dis 1987;6:272-80.

Smith PG. Case-control studies of the efficacy of BCG against
tuberculosis. In: International Union Against Tuberculosis, ed.
Proceedings of the XXVIth IUAT World Conference on Tuberculosis and
Respiratory Diseases. Singapore, Japan: Professional Postgraduate
Services, International, 1987:73-9.

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